Non-stationary 2D NMR - a novel method for studying reaction

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Non-stationary 2D NMR - a novel method for studying reaction mechanism in situ. Ewa K. Nawrocka, Pawe# Kasprzak, Katarzyna Zawada, Jaros#aw Sad#o, Wojciech Grochala, Krzysztof Kazimierczuk, and Piotr J. Leszczy#ski Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b02414 • Publication Date (Web): 06 Aug 2019 Downloaded from pubs.acs.org on August 9, 2019

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Analytical Chemistry

Non-stationary 2D NMR - a novel method for studying reaction mechanism in situ. Ewa Klaudia Nawrocka,†,‡ Pawel Kasprzak,¶,‡ Katarzyna Zawada,‡,§ Jaroslaw Sadlo,‡,k Wojciech Grochala,‡ Krzysztof Kazimierczuk,∗,‡ and Piotr Jerzy Leszczyński∗,,‡ †Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-089 Warsaw, Poland. ‡Centre of New Technologies, University of Warsaw, Banacha 2C, 02-097 Warsaw, Poland. ¶Department of Mathematical Methods in Physics, Faculty of Physics, University of Warsaw, Pasteura 5, 02-093 Warsaw, Poland. §Department of Physical Chemistry, Faculty of Pharmacy with the Laboratory Medicine Division, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland. kInstitute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland. E-mail: [email protected]; [email protected] Abstract Nuclear magnetic resonance spectroscopy (NMR) is a versatile tool of chemical analysis allowing to determine structures of molecules with atomic resolution. Particularly informative are two-dimensional (2D) experiments, that directly identify atoms coupled by chemical bonds or a through-space interaction. Thus, NMR could potentially be powerful tool to study reactions in situ and explain their mechanisms. Unfortunately, 2D NMR is very time-consuming and thus often cannot serve as a ”snapshot” technique for in situ reaction monitoring. Particularly difficult is the case of spectra, in which resonance frequencies vary in the course of reaction. This leads to resolution and

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sensitivity loss, often hindering the detection of transient products. In this paper we introduce a novel approach to correct such non-stationary 2D NMR signals and raise the detection limits over 10 times. We demonstrate success of its application for studying the mechanism of the reaction of AgSO4 -induced synthesis of diphenylmethane-type compounds. Several reactions occur in the studied mixture of benzene and toluene, all with rather low yield and leading to compounds with similar chemical shifts. Nevertheless, with the use of a proposed 2D NMR approach we were able to describe complex mechanisms of diphenylmethane formation involving AgSO4 -induced toluene deprotonation and formation of benzyl carbocation, followed by nucleophylic attacks.

Introduction Nuclear Magnetic Resonance (NMR) is one of the most informative techniques of chemical analysis. Its effectiveness has grown significantly over last decades with an introduction of high-field magnets, cryogenically cooled probes and other improvements. 1 NMR serves well as a method of quantitative and qualitative evaluation of chemical compounds 2 and their mixtures. 2,3 It is also an ideal method to monitor chemical reactions 4 since it provides detailed, atomic-level insight into their mechanisms. In NMR-based reaction monitoring one typically measures changes in chemical shifts and amplitudes of spectral peaks, indicating the changes in structure and dynamics of components of a reaction mixture. Also other spectral features, e.g. diffusion coefficients from diffusion-ordered NMR spectra 5 can serve as descriptors of a reaction progress. Often, the monitoring is performed in situ to detect transitional products, absent in the post-reaction mixture. 6 Reaction monitoring is usually performed using 1H NMR, due to its high sensitivity and short acquisition time of a single spectrum. Two-dimensional (2D) spectra could be even more useful, due to their better resolution and information on the relative positions of atoms. Unfortunately, the measurement of a conventional 2D spectrum requires at least several minutes and thus they usually cannot serve as ”snapshots” of rapid processes. Many 2


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approaches have been proposed to solve the problem, including single-scan acquisition of 2D spectra, 7 fast sampling 8 or encoding reaction kinetics in lineshapes. 9 Importantly for the current study, the non-uniform sampling (NUS) can be useful in this context, 10 since it can shorten the acquisition time of a 2D spectrum several times, depending on its compressability. 11 In NUS approach, only a fraction of sampling points of an NMR signal are collected experimentally, while the rest is reconstructed using algorithms based on various assumptions about the solution. These include: presence of identical dimensions 12 or empty regions, 13 maximum entropy 14 of a spectrum or its maximum sparsity. 15,16 The latter is the principle behind currently the most common reconstruction method referred to as compressed sensing (CS) 15,16 having range of applications reaching far beyond NMR field 17 and being related to several other methods. 18–21 It has been shown, that CS can shorten the acquisition time of 2D spectra allowing to use them as ”snapshots” of the reaction. 22 The variant of NUS dedicated for reaction monitoring is time-resolved NUS (TR-NUS), where overlapping subsets of the NUS dataset collected during the reaction are processed - either separately 23 or co-processed together. 24 The resulting stack of spectra provides a picture of studied changes with temporal resolution comparable to that obtained from 1H NMR. 22 Chemical reactions resulting in gradual changes of chemical shifts of the reactants are particularly difficult to follow using 2D NMR. Even if the changes are slow enough in the time-scale of a direct dimension of 2D spectrum, they can make Fourier transform (FT) in the indirect dimension impossible, or at least result in significant t1 -noise. Similar effects are caused by slow drifts of external magnetic field and can be suppressed by lock systems or external devices. 25 In this paper, we show two NMR approaches to studying the reactions that affect the positions of spectral peaks: model-based i.e. assuming certain simple shape of variations and model-free, i.e. based on the information from 1D data interleaved with 2D NUS data. Both allow to reveal, otherwise undetectable, peaks that are crucial to understand the reaction mechanism.

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The reaction under study is the synthesis of diphenylmethane from toluene and benzene induced by AgSO4 . The oxidative C-C coupling reactions of aromatic and alkylaromatic compounds proceeded by direct oxidative C-H bond activation are excellent tools for syntheses of substituted diphenylmethanes, especially because typically no functionalization of the substrates is necessary. 26,27 Applications of transition metals compounds - especially Pd(II) 28–35 and Cu(II) 36–43 catalysed C-H bond activation have emerged as a successful synthetic methodology for this chemistry, but the use of Ag(II)- an open shell [Kr]4d9 system isolelectronic with Cu(II) has not been extensively investigated. 44,45 On the other hand, reactions involving AgF2 and other fluoro Ag(II) species, lead to exhaustive fluorination of organic compounds rather than C-C coupling. 46–49 AgSO4 50 is a very strong one-electron transfer containing true divalent silver cation (Ef ≈ +2.9 V vs. NHE), 51 which is capable of room-temperature activation C-H bonds (followed by C-C coupling). 52,53 Reconnaissance of reactivity of AgSO4 oxidizer proved usability of this compound in binaphthyl derivatives formation via sp2 -sp2 C-C coupling of the corresponding naphthalene moieties and for activation of C-H bonds in F – and/or CF3 – group substituted aromatic compounds that are unreactive in classical C-H bond activation protocols (followed by C-C coupling) single-pot system albeit with rather low yields. 52,53 Importantly, since the reaction involves solid AgSO4 at the bottom of NMR tube (see Figure S6 in Supporting Information) and a spin trap solution added from the top, the distribution of products can be slightly inhomogenous and thus single-scan methods based on slice-selective excitation 7 may not be optimal. Moreover, although such approaches could minimize the effect of non-stationarity, the benefit would come at the cost of sensitivity and lead to loss of potentially informative weak peaks. However, when sensitivity is not an issue and the sample is homogeneous, they might be superior to the presented method. Here we report the study of the mechanism of AgSO4 -induced direct synthesis of diphenylmethanetype compounds from benzene-toluene mixture. Since application of the previously introduced approaches 22,54 did not lead to detection of some important signals in 2D NMR spectra,

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here we introduce novel protocol for time-resolved measurements of correlation spectra. The method is based on standard pulse sequences and the acquisition is performed using free and well-documented TReNDS software 54 .

Experimental Reagents and reaction AgSO4 was obtained electrochemically using published procedure. 55 Analytical grade (nominal purity 99+%) reactants and solvents were purchased from Sigma-Aldrich and dried over molecular sieve 4 ˚ A before use. The purity of organic substrates was checked using tandem GC/MS technique. Also identification of products in post-reaction mixtures uses the same analytical methodology. All GC/MS measurements were performed commercially in the Institute of Organic Chemistry (Polish Academy of Science). Agilent 7890A & 5975 spectrometer with capillary column HP-5MS and NIST 08 database were used in all cases. Samples for NMR and GC/MS measurements were prepared under inert argon atmosphere in Labmaster DP MBRAUN glovebox (O2 < 0.1 ppm; H2 O< 0.1 ppm) (see Figure S1 in Supporting Information). Typical sample preparation procedure: 35 µl of benzene (0.4 mM) and 15 µl toluene (0.13 mM) were dissolved in 900 µl of nitromethane-d3 . 13 mg (0.064 mM) AgSO4 was weighed directly in NMR tube. Subsequently, 500 µl of solution were added at 25° C in argon atmosphere of a glovebox chamber and the NMR tube was immediately frozen using liquid nitrogen to facilitate transfer to the spectrometer. Before NMR measurements reaction mixture was warmed up to 25°C and process was monitored for 72 h. Due to lack of solubility of silver(II) sulphate in any of organic solvents, the room temperature Ag(II)-induced C-H bond activation proceeds at the solid-liquid interface. In all performed experiments, reactivity of the AgSO4 has been examined using NMR and GC/MS identification of products in post-reaction mixtures.

NMR and EPR measurements The measurements were performed on 700 MHz Agilent DirectDrive2 spectrometer equipped with a room-temperature HCN probe, temperature5



controlled at 25 °C. For blank test, a sample containing only AgSO4 and nitromethane-d3 was monitored for 72 h (see Supporting Information). The reaction was initiated in a following way: 800 µl of a standard benzene-toluene solution in nitromethane-d3 was prepared, after which the solution was divided into two parts. In the first part, about 3 mg of the spin trap (N-tert-butyl-alpha-phenylnitron, PBN spin trap) were dissolved, while the second part of the solution was used to initiate the reaction. After 5 minutes from the initiation of the reaction, a solution with PBN spin trap was added. The reaction was monitored for about 72 h using the TR-NUS method in which 1

H NMR spectra were interleaved with t1 points of 2D HSQC spectra. The TR-NUS has to

be performed with shuffled sampling. We used 36864 NUS points from non-decaying pseudorandom distribution covering grid of 256 points. gHSQCAD pulse sequence from VnmrJ 4.2 software was used with acquisition macros from TReNDS software package. 54 The reaction was repeated and monitored using electron spectroscopy paramagnetic resonance (EPR) in organic excitation and wide excitation band of 1000 MHz. The sample for the measurements was prepared in the same way as for NMR. After adding the PBN spin trap solution to the reaction mixture, the solution without solid AgSO4 was taken to the capillary. For interleaved 1D 1H NMR spectra the following acquisition parameters were used: number of transients = 1, interscan delay = 1 s, 32K complex points and acquisition time = 2.94 s. For 2D ROESY spectrum: number of transients = 32, number of t1 increments = 512, number of FID complex points = 1674 and acquisition time = 0.15 s, interscan delay = 1 s, mixing time 300 ms. For TR-NUS HSQC spectrum every NUS point was registered with a number of transients = 2, number of FID complex points = 1674, acquisition time = 0.15 s, interscan delay of 1 s and a full grid of 256 points. Additionally, we measured quantitative 1D spectrum of post-reaction mixture (results in Table 1) with the following parameters: number of transients = 32, interscan delay = 90 s, 32K complex points and acquisition time

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= 2.94 s. The maximum T1 relaxation time, measured with inversion-recovery experiment, was 18 s for benzaldehyde (long, since the sample was prepared in argon atmosphere). Thus, we set inter-scan delay in the quantitative 1D spectrum to 90 s. EPR spectra were recorded using X-band Bruker EMXplus cw spectrometer with a modulation frequency of 100 kHz, a cylindrical cavity and 10 mW microwave power. Center field was 3520 G and conversion time was 30 s. Instrumental settings were: 1.0 G modulation amplitude with 20 Pts/Modulation Amplitude, 1.28 s time constant, 100 G field width, 60 s sweep time per scan, 16 scans. 2000 points were acquired. The reaction was also monitored without using PBN spin trap, where samples were prepared as described above. Description of monitoring and the results was described in Supporting Information (see paragraphs: Monitoring of the reaction without spin trap and Monitoring of the reaction using isotopically labelled substrates). The blank tests were also carried out to eliminate the background from capillaries, the solvent itself and AgSO4 . 2D rotating frame nuclear Overhauser effect spectra (ROESY) of a post-reaction mixture, with a spin trap, were recorded with a spin lock time of 300 ms. A spectral width of 15.9 ppm was used in both dimensions. Conventional sampling with 512 complex points in t1 and 3348 complex points in t2 was performed. 32 scans per point and 32 stead-state scans were used. A relaxation delay between scans was 1 s. 2D diffusion-ordered (DOSY) spectra of a post-reaction mixture (with and without using a spin trap) were collected using the bipolar pulse pair stimulated echo pulse sequence from VnmrJ 4.2 and 15 gradient values (gradient length of 2 ms and diffusion delay of 50 ms). Data were processed by ITAMeD software. 56 1000 iterations were used with a grid of 256 diffusion coefficients ranging from 10−7.5 to 10−9.5

m2 s

and λ was 1e−5 .

The obtained 1D and 2D data sets were Fourier transformed and processed using nmrPipe, 57 Mnova 12.0 and Sparky software. 58 The NMRBox resources were used to deal with large sets of 1D data. 59

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Correcting non-stationary 2D NMR signals The mathematical model of a free induction decay (FID) signal that can be found in most NMR textbooks assumes the resonance frequencies not to vary with time. For example, 2D NMR signal s(t1 , t2 ) with one pair of correlated frequencies (ν1 , ν2 ) that are stationary (i.e.

∂νi ∂tj

= 0 for every i, j = 1, 2) is given

by

s(t1 , t2 ) = exp(2π ι˙ν1 t1 ) exp(2π ι˙ν2 t2 )

(1)

Changing chemico-physical conditions during the signal acquisition can be reflected by the non-stationarity of one or more frequencies:

∂νi ∂tj

6= 0 for some i, j = 1, 2. However, in the

examples below, the changes are slow enough to assume that both ν1 and ν2 are stationary with respect to t2 . Regarding the indirect dimension, it is worth to express the dependence on t1 in terms of the increment indices ind(t1 ) in a NUS schedule instead of t1 itself. This is because ind(t1 ) rather than t1 changes linearly with the reaction time. Two 2D NMR experimental contexts that appear in the present study yield different kind of non-stationarity: 1. 2D TR-NUS

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C HSQC spectrum for reaction monitoring. In this case, the non-

stationarity (in particular of ν2 ) leads to a heavy deformation of the corresponding spectra. In the extreme cases, observed in our work, the broadened non-stationary peaks may disappear under the noise. Remarkably, the non-stationarity can effectively be corrected on the basis of 1D spectra measured in-between of acquisition of 2D NUS points, provided that the peak overlap in 1D does not completely hamper the determination of resonance frequency of a shifting peak. This allows for the estimation and correction of ind(t1 )-dependence of ν2 in 2D FID. The correction scheme is presented in Figure 1. The corresponding MATLAB script is described in Supporting Information. In brief, the processing scheme is as follows: FT

• 2D FID s(t1 , t2 ) is Fourier transformed in t2 : s(t1 , t2 ) −→ S(t1 , f2 ); 8


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• the dependence of ν2 on ind(t1 ) is established based on 1D spectra measured between every 2 hypercomplex NUS points (every 4th FID of HSQC); • the linear form of correction of ν2 is assumed between consecutive 1H spectra; • the correction is applied to keep all signals S(t1 , f2 ) in a given frame of TR-NUS dataset aligned with respect to f2 . The corrected datasets are processed in the standard TR-NUS manner: first divided into ”frames” and then missing points are reconstructed using CS algorithm (iterative soft thresholding, IST). 22,23 The correction procedure allows to deal with frequency variations within TR-NUS frames, which is a significant improvement comparing to previous work by Dass et al. 22 which allowed strong variations to occur between, but not within, frames. 2. Post-reaction 2D ROESY spectrum with conventional sampling. Fourier transform applied to the corresponding 2D FID reveals peaks deformed due to frequency variation (which, as seen from 1D spectra, may be attributed to shifts of resonance frequency of spin adduct (10a in Figure 5) and HSO4 – ion pair). Unlike in the 2D TR-NUS HSQC case, they are not covered by noise. However, their non-Lorentzian shape hampers the integration and thus quantitative analysis. We propose the following procedure correcting deformed peaks (for the pictorial description see Figure 2): FT

• 2D FID s(t1 , t2 ) is Fourier transformed in t2 : s(t1 , t2 ) −→ S(t1 , f2 ); • first correction modifies f2 by shifting S(t1 , f2 ) by 1 f2 t1 + 2 f2 t21 , which aligns peaks that shift according to this quadratic model (and desynchronises all others). The linear and quadratic coefficients are determined by maximizing the highest data point in a resulting 2D spectrum. • second correction is applied to those peaks that are still deformed after the first correction, since their ν1 (frequencies in the indirect dimension) also depend on

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t1 . In this case the linear correction of f1 by 1 f1 t1 effectively modifies the data, correcting the observed non-stationarity in agreement with the ”semi - Radon” model as developed in. 60 Similarly as in that paper, the appropriate correction can be recognized by Lorentzian lineshape and 1 f1 can be found by brute-force maximization of the peak amplitude. Notably, the first step of the procedure resembles a method proposed very recently for correcting the magnetic field drift effect in solid state NMR spectra. 61 Of course, the quadratic form of a peak shift has no physical interpretation, but for the examples shown in this study it approximated the actual changes sufficiently well. In fact, most of types of NMR non-stationarity stem from shifting chemical exchange equilibria and thus follow exponential models, that can be well approximated with simple polynomials. Importantly, both correction procedures align non-stationary peaks, but deform the stationary ones at the same time. Thus, the processing has to be repeated for every spectral region containing non-stationary peaks and the results have to be analyzed simultaneously with the result of conventional processing (no correction). In the case of strong peak overlap in 2D, the ”deformed peaks” may constitute a background distortion for nearby resonances. Such situation, however, was not observed in our study (although might be common in general). The processing uses compressed sensing function from mddnmr-package 62 and ”aligning” (or ”straightening”) script written in MATLAB. The description of processing scripts for both TR-NUS 2D HSQC and conventional 2D ROESY can be found in Supporting Information.

Results and discussion Correction for non-stationarity The 2D TR-NUS

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C HSQC spectra acquired with

the addition of a spin trap contain peaks that rapidly change their position in the course 10


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Intensity, a.u.

2

xx 10 1044 1

1.5

0.5 0 10 8

f2 -

6

1 H

4

(pp

m)

2 0

3

2

0

127 128

4

129 130

131 132

Number of NUS point

2

Intensity, a.u.

2

Intensity, a.u.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


4 10 xx 10 1.5

4

1 0 10 f2 - 81 6 H (p 4 2 pm )

0 0

1

3 2 S point Number of NU

x 104 1.5

1 0 10

4

8 f2 - 1 6 H 4 (p pm 2 )

0

0

1

3 2 S point Number of NU

4

Figure 1: The idea of straightening 2D TR-NUS FID based on the interleaved 1H NMR spectra. Subsets (”frames”) are aligned with respect to the first FID in each subset. 1H NMR are marked with green, while real and imaginary parts of indirect dimension 2D FID with blue and red, accordingly. Notably, the correction procedure straightens the shifting peak at ca. 6 ppm but disturbs the stationary peak at ca. 8 ppm. Thus, both corrected and uncorrected spectra have to be used for analysis.

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15

Ti 10 m e( m

1

in 5 )

0 7

5

6

3 ) pm

4

2

f 2 (p

Using simple polynominal (quadratic) model of a change of peak position - correction without support from interleaved 1D spectra

15

Ti 10 m e( m

1

in )

5 0 7

5

6

3 ) pm

4

2

f 2 (p

Figure 2: Straightening the data from conventionally sampled 2D experiment. The 2D FID after FT in the direct dimension is aligned to remove changes of resonance frequency in direct dimension (f2 ) over time of a reaction (and thus with t1 ). The alignment is based on a simple polynomial fit that maximizes the resulting peak intensity. Notably, the correction procedure straightens the shifting peak at ca. 4 ppm but disturbs the stationary peak at ca. 6 ppm. Thus, both corrected and uncorrected spectra have to be used for analysis.

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of a reaction, in particular in the direct ( 1H) dimension. As explained below, these peaks belong to the spin adduct formed by an reaction intermediate and a spin trap and thus it is important to follow its formation. This is impossible without ”straightening the data” i.e. removing the dependence of 1H resonance frequency on indirect evolution time. The result of the use of straightening algorithm is presented in Figure 3 (additionally, the undesired effect of correction for stationary peak is shown). The first of reconstructed frames in the TR-NUS dataset are compared: raw (uncorrected) and corrected for nonstationarity. The correction factor was obtained as explained in the Methods section, i.e. by monitoring 1H frequency with 1D spectra. Peak belonging to the reaction intermediate is severely broadened and thus it is hidden under the noise. The correction based on 1D spectra interleaved with NUS of the indirect dimension reveals the peak and allows to identify the reaction intermediate ”on-the-fly”, during the reaction. Importantly, the proposed method of correction does not require the peak to be visible in separate FIDs of 2D NUS dataset. In addition, an increase in the detection limit, which is over 10 times, could be estimated from 1D spectra (change in chemical shift to half-width of the peak). The peak intensities from a post-reaction 2D ROESY spectrum with conventional sampling are used to determine internuclear distances (see e.g. 63 ). The results of our calculations can be seen in paragraph ROESY experiment in Supporting Information. Thus, it is crucial to obtain good lineshapes, that can be fitted and integrated. As can be seen in Figure 4a, some peaks in 2D ROESY spectrum of a post-reaction mixture do not fulfill this requirement. The deformation originates from the shift of resonance frequency of a peak at ca. 10.3 ppm, that occurs during sampling of indirect evolution time t1 . The shift occurs due to the fact, that the equilibrium of HSO4 – -spin-adduct complex formation depends strongly on the temperature and is established slowly after the sample is moved from the laboratory (20 °C) to measurement conditions (ca. 25 °C). This happened, since the sample was put back into the magnet several days after the reaction. The situation may occur in many other practical cases, e.g. in temperature-jump NMR experiments. The temperature dependence

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One of the reconstructed frames of HSQC spectrum WITHOUT using straightening method

x 103 5 4 3 2 1 0

One of the reconstructed frames of HSQC spectrum AFTER using straightening method

x 103 5 4 3 2 1 0

f1 13 72 68 C (p pm )

4.8 4.7 64 5.2 5.1 4.9 ) 1 H (ppm

f1 - 13 72 C (p 68 pm ) x 104

4.6 4.5

f 2-

4

x 10

d

Intensity, a.u.

c

b Intensity, a.u.

Intensity, a.u.

a

Intensity, a.u.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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5 4 3 2 1

64

4.7 4.6 4.9 4.8 5.1 5.2 1 H (ppm)

4.5

f 2-

1 0.8 0.6 0.4 0.2 0

0

f1 - 138 13 7.5 7.4 C 134 7.7 7.6 (p 7.8 pm 130 8.0 7.9 1 (ppm) ) f 2- H

f1 - 138 13 7.5 7.4 C 134 7.7 7.6 7.8 (p pm 130 8.0 7.9 1 (ppm) ) f 2- H

Figure 3: Reconstructed first frames of 2D TR-NUS HSQC spectra. Panels show regions with non-stationary and stationary peaks. a) Non-stationary peak without correction for 1H frequency shift; b) the same peak after using ”straightening” algorithm taking 1H coordinates from 1D spectra interleaved with 2D NUS points; c) stationary peak before correction; d) the same peak disturbed by the correction. Both corrected and uncorrected spectra have to be used for analysis.

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of a peak-position has been studied separately with a series of 1H NMR spectra, shown in Supporting Information (Section Reasons for non-stationarity in ROESY ). The shift for 2 = 6 0 , and can off-diagonal peaks occurs only for direct-dimension resonance frequency ∂ν ∂t1 be corrected by aligning peaks obtained Fourier transform in a direct dimension S(t1 , f2 ). As described in the Methods section, the approach assumes simple polynomial model of a change and finds right linear and quadratic terms by maximizing the peak intensity in a resulting 2D spectrum. The effect of correction on stationary peaks, also mentioned in the Methods section, is shown in Figure 4e) and f). We found the quadratic model sufficient the quadratic term improved the peak height by further ca. 3.5% comparing to solely linear correction, but cubic term did not provide any more gain.

For diagonal peak the frequency non-stationarity can be observed in both dimensions ∂ν2 ∂ν1 = 6 0, = 6 0 . The correction applied as described in the Methods section, leads to ∂t1 ∂t1

proper Lorentzian lineshapes and quantitative conclusions (see below).

Identification products of the reaction To identify the reaction products, one- and two-dimensional spectra were acquired (1D 1H, 1D

13

C, 2D HSQC, 2D HMBC, 2D Z-

TOCSY). The main product, diphenylmethane and 4 other products, have been found, matching also the results from GC-MS. Quantitative 1H NMR spectrum allowed to determine the yield of this reaction (see Table 1). The table shows chemical shifts of linkers between phenyl rings (-CH2 - groups) and -CH3 groups of the above compounds. The yield of the reaction was calculated based on the amount of one of the substrates - toluene (see Supporting Information).

Monitoring of the reaction with and without a spin trap During monitoring of reaction with and without adding a spin trap, most reaction products are seen already in the first spectrum. The peaks (singlets) belonging to the diphenylmethane, 2-methyldiphenylmethane, 4-methyldiphenylmethane, 2,2’-dimethyltriphenylmethane -CH2 - linkers and their -CH3 groups and also a peak belonging to benzaldehyde were observed in the very first 1H spectrum ac15



1

1

b

a

10.20

3

d

e

f

3

10.25

10.30

5

10.20

f1- 1H (ppm)

f1- 1H (ppm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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c

10.25

7

5

7

10.30

10.34

9

11

f

10.30

_ 1H (ppm) 2

9

11

10.50 10.50 1 f H (ppm) 2

_

8.50 8.50 1 f H (ppm) 2

_

Figure 4: The results of a two-step procedure for ”straightening” 2D ROESY spectrum. a) spectrum with peaks deformed due to FID non-stationarity Fragment of uncorrected ∂ν2 ∂ν1 6= 0, ∂t1 6= 0 ; b) After removing the dependence of ν2 on t1 off-diagonal peaks be∂t1 come Lorentzian-shaped; c) The zoomed-in diagonal peak region showing deformation due 1 6= 0); d) Corrected diagonal peak; e) Fragment of uncorrected spectrum with stationto ( ∂ν ∂t1 ∂ν2 ∂ν1 ary peaks (not deformed) ∂t1 = 0, ∂t1 = 0 ; f) The same peaks, deformed after correction for non-stationarity of ν2 . Both corrected and uncorrected spectra have to be used for analysis.

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Table 1: Yield of the identified reaction products with respect to toluene substrate. Number Product’s in Figure 7 name 3 Diphenylmethane 4 2-Methyldiphenyl-methane 5 4-Methyldiphenyl-methane 8 Benzaldehyde 7 2,2’-Dimethyltriphenyl-methane

Chemical shift, Yield (W), ppm % Linker: 4.00 0.71 Linker: 4.03 0.45 -CH3 group: 2.28 Linker: 3.95 0.55 -CH3 group: 2.30 Singlet around 10.00 2.05 Linker: 5.60 0.21 -CH3 groups: 2.32

quired during the reaction. A peak moving towards higher chemical shifts in the course of reaction was also present in the first spectrum. Its chemical shift changed from ca. 7.50 ppm to ca. 11 ppm over the 72 h (see Figure S1 in Supporting Information), though it differed depending on the sample. The peak probably belongs to the HSO4 – ion interacting with carbocation (see 1b in Figure 7). In 2D HMBC and 2D HSQC it was not correlated with any

13

C atoms nor with other 1H atoms. Change of chemical shift during the monitoring of

the reaction probably results from the change in pH. Another non-stationary peak, probably belonging to reaction intermediate, has been observed at ca. (72 ppm, 5.25 ppm). The intensity of that peak decreased with the progress of the reaction (see Figure S2 and Figure S3 in Supporting Information). It probably comes from -CH2 group of benzyl radical, a reaction intermediate. The reaction with addition of a spin trap occurred in a visibly different manner. Firstly, the reduced yield manifested itself by less intense color of a post-reaction mixture. Secondly, the turbidity of the solution was observed quickly after adding a spin trap (see Figure S8 in Supporting Information). It is caused by reduced spin adduct’s solubility in nitromethane. A change in the color in the initial stage of a reaction indicates the trapping of the benzyl radical (which has a yellow-amber color) by a PBN spin trap (see Figure S8 in Supporting Information).

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From 1H NMR and 2D TR-NUS HSQC acquired during the reaction after an addition of a spin trap one can see, that peaks belonging to the spin trap change their chemical shift over time. Peaks of all products were also observed. In the final stage of the monitoring, peaks belonging to the spin trap hydrolysis products (iso-octane, benzonitrile) were observed. A characteristic peak with a changing chemical shift during reaction (9.4-11.0 ppm - see Figure S7 in Supporting Information) was also noticed. Particularly interesting peak at ca. (72 ppm, 5.25 ppm), which belongs to the reaction intermediate, changed its chemical shift after adding solution of the spin trap (see Figure S7 in Supporting Information). It can be revealed only after application of ”straightening” algorithm. The change in chemical shift can be explained by trapping a benzyl radical by a spin trap. The peak belongs to the -CH2 group of the benzyl radical forming an spin adduct with the spin trap. It is also present in the spectrum of the post-reaction mixture. Importantly, peaks belonging to the spin adduct can be observed due to the very fast oxidation of the radical spin adduct by AgSO4 . The spin adduct is probably a cation, because on the 2D ROESY spectrum correlations peaks with the peak belonging to the probable HSO4 – ion are observed. The proposed reaction mechanism between the spin trap 9 and the benzyl radical 1a is presented in Figure 5. As a result of oxidative action of AgSO4 spin adduct 10 is transformed to carbocation 10a. The presence of a benzyl radical (1a in Figure 5) was confirmed by EPR experiments (see Supporting Information for results). In the 2D Z-TOCSY spectra, we do not observe correlation peaks of the HSO4 – ion. We also observe peaks which probably belong to the spin adduct’s hydrolysis products. ROESY experiment In the 2D ROESY spectrum, the correlation peaks between HSO4 – ion and peaks belonging to spin trap in the spin adduct could be seen. However, they are deformed due to variations of resonance frequencies over the course of experiment (i.e. with t1 ). However, thanks to implementation of straightening algorithm, their intensities and

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Figure 5: AgSO4 -based reactions involving toluene and N-t-butyl-alpha-phenylnitrone spin trap molecules. thus internuclear distances can be determined. In our case, internuclear distances between hydrogen in HSO4 – and hydrogens in spin adduct could be destignated - 2.10 and 2.70 ˚ A (see details in ROESY experiment in Supporting Information). Additionally, EXSY correlation peaks could be seen, differing from other off-diagonal peaks in sign of their intensity (see Figure 4a)). This may indicate the proton exchange between HSO4 – ion and -NH fragment of protonated PBN spin trap (9.98 ppm) (see equation below). The rate of chemical exchange of a proton between HSO4 – and -NH fragment could be calculated according to 64,65 (see the Supporting Information). Thanks to the straightening algorithms, the intensity of EXSY peak and diagonal peak of HSO4 – could be designed. Magnetization exchange rate constants provide that equilibrium is shifted towards HSO4 – ion. Notably, the exchange is fast on the timescale of an NMR experiment. The rates of a exchange: k0

1 − → HSO4 – − ← − − − NH fragment of protonated PBN spin trap 0

k−1

19



are as follows: k’1 is 8.65 Hz k’−1 is 20.23 Hz

DOSY experiments The diffusion spectra of the post-reaction mixtures with and without PBN spin trap were also acquired. Without PBN spin trap, an HSO4 – ion revealed much slower diffusion rate than nitromethane and even slightly slower than aromatic compounds. With PBN spin trap, a spin trap in spin adduct moved slightly slower than (complexed) HSO4 – ion and nitromethane. The results, presented in Figure 6, confirm all the above conclusions regarding a mechanism and a presence of HSO4 – complexed with spin adduct formed by benzyl radical and PBN spin trap. It should be emphasized that DOSY and ROESY spectra were used to study the final product of the reaction, not the mechanism of its formation (interleaved 1D and 2D HSQC spectra served for this purpose).

Proposed mechanism of reaction To summarize obtained results we propose mechanism of diphenylmethanes compounds formation. The first step of diphenylmethane 3 formation is very fast and likely corresponds to outer-sphere electron transfer 53 from toluene 1 molecule to surface of AgSO4 and subsequent deprotonation of obtained organic radical cation which results in benzyl radical 1a formation. Formal E◦ potentials for benzene/benzene radical cation and toluene/toluene radical cation redox couples are equal 2.90 and 2.64 V vs. NHE respectively. 66 Formal potential for benzyl radical/benzyl carbocation redox couple is ca. 0.40 V vs. NHE, 67 which probably response for the absence of phenyl radical. Formal potential for Ag(II)/Ag(I) redox couple is ca. 2.90 V vs. NHE, which probably corresponds to easier oxidation of benzyl radical for benzyl carbocation than phenyl radical to phenyl carbocation. Thus, toluene molecule in benzene-toluene mixture is easier oxidized by Ag(II), as indicated by much higher content of toluene by benzene units in the products 20


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HSO4benzene solvent (nitromethane-d3)

9.500 9.375 9.250

9.125 9.000 8.875 8.750 8.625 8.500 8.375 8.250 8.125 8.000 7.875 7.750 7.625 -logD, m2/s

spin trap (8.65 ppm)* intermediate product* spin trap (8.35 ppm)* solvent (nitromethane-d3)

HSO4-

* in spin adduct

9.500 9.375 9.250

9.125 9.000 8.875 8.750 8.625 8.500 8.375 8.250 8.125 8.000 7.875 7.750 7.625 -logD, m2/s

Figure 6: Diffusion profiles from DOSY spectra of post-reaction mixture without (top) and with spin trap.

21



as well as by complete absence of an substituted by phenole. The next step is very fast electron transfer from benzyl radical 1a to surface of AgSO4 and formation of benzyl carbocation 1b. Extremely reactive benzyl carbocation 1b attacks neutral benzene 2 or toluene 1 molecule according to classical nucleophilic substitution and form diphenylmethane systems after proton loss 3-6. Benzyl carbocation 1b is also able to attack obtained products 3-6 with formation of substituted triphenylmethanes compounds (for example 7)- see Figure 7. Benzaldehyde 8 is also present in a post-reaction mixture as a product of AgSO4 induced toluene 1 oxidation. The low yield of overall reaction is supposedly related with the necessity of deprotonation of organic intermediate which is hindered by the presence of H2 SO4 . A change in the solution’s pH, caused by sulfuric acid leached out of the AgSO4 precipitate and HSO4 – generated by the reaction mechanism, causes inhibition of deprotonation of the benzyl carbocation and intermediates, which is associated with decreased yield.

Conclusions The AgSO4 -induced synthesis of diphenylmethane presented in this work is an example of a process difficult to monitor with NMR. Presence of multiple parallel sp2 -sp3 C-C coupling reaction pathways, low yield, varying resonance frequencies of the products and complex composition of a reaction mixture constitute challenges for both 1D and 2D spectroscopy. We have demonstrated how these methods can be used in a complementary manner and how information from 1D spectra can be used to correct distortions in non-uniformly sampled 2D spectra by ”straightening” the non-stationary signal. Moreover, similar algorithms can help to correct conventionally sampled spectra, e.g. 2D ROESY and provide credible information on distances and exchange rates in dynamic spin adducts of molecules. Here we have demonstrated for the first time how with the help of non-stationary 2D NMR we proposed the mechanism of monitored reaction and the structure of reaction intermediate - a benzyl radical. Moreover, with non-stationary 2D spectra we proved a presence of a

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Figure 7: AgSO4 -based reactions observed in this study, involving toluene and benzene molecules.

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complex between HSO4 – and spin adduct formed by benzyl radical and spin trap. The methods for dealing with non-stationary 2D NMR signals can be applied in a variety of experiments and provide significant sensitivity and resolution gains. Results suggest, that they can be particularly useful in case of reacting samples.

Acknowledgement This study made use of NMRbox: National Center for Biomolecular NMR Data Processing and Analysis, a Biomedical Technology Research Resource (BTRR), which is supported by NIH grant P41GM111135 (NIGMS). 59 EKN, PK and KK thank the Foundation for Polish Science for support from FIRST TEAM programme co-financed by the European Union under the European Regional Development Fund no. (First TEAM/2017-4/34). PJL thanks the National Science Centre of the Republic of Poland (NCN) for OPUS grant (UMO-2015/19/B/ST5/02863).

Supporting Information Available Supporting Information include the following: description and links to MATLAB scripts, details on reagents and reaction (also with isotopically labelled substrates), experimental details of EPR experiment and ROESY calculations.

References (1) Kovacs, H.; Moskau, D.; Spraul, M. Cryogenically cooled probesa leap in NMR technology. Prog. Nucl. Magn. Reson. Spectrosc. 2005, 46, 131–155. (2) Bharti, S. K.; Roy, R. Quantitative 1H NMR spectroscopy. TrAC - Trends in Analytical Chemistry 2012, 35, 5–26.

24


Page 24 of 32

Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(3) Rodr´ıguez, F. J.; Schlenger, P.; Garc´ıa-Valverde, M. Monitoring changes in the structure and properties of humic substances following ozonation using UV-Vis, FTIR and 1H NMR techniques. Sci. Total Environ. 2016, 541, 623–637. (4) Maiwald, M.; Fischer, H. H.; Kim, Y.-k.; Albert, K.; Hasse, H. Quantitative highresolution on-line NMR spectroscopy in reaction and process monitoring. J. Chem. Inf. Model./Introduction 2004, 166, 135–146. (5) Urba´ nczyk, M.; Bernin, D.; Czuro´ n, A.; Kazimierczuk, K. Monitoring polydispersity by NMR diffusometry with tailored norm regularisation and moving-frame processing. Analyst 2016, 141, 1745–1752. (6) Foley, D. A.; Dunn, L.; Zell, M. T. Reaction monitoring using online vs tube NMR spectroscopy : seriously different results. J. Chem. Inf. Model./Introduction 2016, 54, 451–456. (7) Gal, M.; Mishkovsky, M.; Frydman, L. Real-time monitoring of chemical transformations by ultrafast 2D NMR spectroscopy. J. Am. Chem. Soc. 2006, 128, 951–956. (8) Ndukwe, I. E.; Shchukina, A.; Kazimierczuk, K.; Butts, C. P. Rapid and safe ASAP acquisition with EXACT NMR. Chem. Commun. 2016, 52, 12769–12772. (9) Balbach, J.; Forge, V.; Lau, W. S.; van Nuland, N. a.; Brew, K.; Dobson, C. M. Protein folding monitored at individual residues during a two-dimensional NMR experiment. Science (New York, N.Y.) 1996, 274, 1161–1163. (10) Wu, Y.; D’Agostino, C.; Holland, D.; Gladden, L. In situ study of reaction kinetics using compressed sensing NMR. Chem. Commun. 2014, 50, 14137–14140. (11) Shchukina, A.; Kasprzak, P.; Dass, R.; Nowakowski, M.; Kazimierczuk, K. Pitfalls in compressed sensing reconstruction and how to avoid them. J. Biomol. NMR 2017, 68, 79–98. 25



(12) Br¨ uschweiler, R.; Zhang, F. Covariance nuclear magnetic resonance spectroscopy. J. Chem. Phys. 2004, 120, 5253–5260. (13) Matsuki, Y.; Eddy, M. T.; Herzfeld, J. Spectroscopy by integration of frequency and time domain information for fast acquisition of high-resolution dark spectra. J. Am. Chem. Soc. 2009, 131, 4648–4656. (14) Mobli, M.; Hoch, J. C. Maximum entropy spectral reconstruction of nonuniformly sampled data. Concepts Magn. Reson., Part A 2008, 32, 436–448. (15) Kazimierczuk, K.; Orekhov, V. Y. Accelerated NMR spectroscopy by using compressed sensing. Supporting Information. Angew. Chem., Int. Ed. 2011, 50, 5556–9. (16) Holland, D. J.; Bostock, M. J.; Gladden, L. F.; Nietlispach, D. Fast multidimensional NMR spectroscopy using compressed sensing. Angew. Chem., Int. Ed. 2011, 50, 6548– 6551. (17) Holland, D. J.; Gladden, L. F. Less is more: How compressed sensing is transforming metrology in chemistry. Angew. Chem., Int. Ed. 2014, 53, 13330–13340. (18) Barna, J. C. J.; Tan, S. M.; Lade, E. D. Use of CLEAN in conjunction with selective data sampling for 2D NMR experiments. J. Magn. Reson. (1969) 1988, 78, 327–332. (19) Stanek, J.; Ko´zmi´ nski, W. Iterative algorithm of discrete Fourier transform for processing randomly sampled NMR data sets. J. Biomol. NMR 2010, 47, 65–77. (20) Coggins, B. E.; Zhou, P. High resolution 4-D spectroscopy with sparse concentric shell sampling and FFT-CLEAN. J. Biomol. NMR 2008, 42, 225–239. (21) Qu, X.; Mayzel, M.; Cai, J. F.; Chen, Z.; Orekhov, V. Accelerated NMR spectroscopy with low-rank reconstruction. Angew. Chem., Int. Ed. 2015, 54, 852–854. (22) Dass, R.; Ko´zmi´ nski, W.; Kazimierczuk, K. Analysis of complex reacting mixtures by time-resolved 2D NMR. Analytical Chemistry 2015, 87, 1337–1343. 26


Page 26 of 32

Page 27 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(23) Bermel, W.; Dass, R.; Neidig, K. P.; Kazimierczuk, K. Two-dimensional NMR spectroscopy with temperature-sweep. ChemPhysChem 2014, 15, 2217–2220. (24) Mayzel, M.; Rosenlöw, J.; Isaksson, L.; Orekhov, V. Y. Time-resolved multidimensional NMR with non-uniform sampling. J. Biomol. NMR 2014, 58, 129–139. (25) Kazimierczuk, K.; Ko´zmi´ nski, W. Efficient compensation of low-frequency magnetic field disturbances in NMR with fluxgate sensors. J. Magn. Reson. 2005, 174, 287–91. (26) Doucet, H.; Hierso, J. C. Palladium-based catalytic systems for the synthesis of conjugated enynes by sonogashira reactions and related alkynylations. Angew. Chem., Int. Ed. 2007, 46, 834–871. (27) Grzybowski, M.; Skonieczny, K.; Butenschön, H.; Gryko, D. T. Comparison of Oxidative Aromatic Coupling and the Scholl Reaction. Angew. Chem., Int. Ed. 2013, 52, 9900– 9930. (28) Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides. Tetrahedron Lett. 1979, 20, 3437–3440. (29) Chercka, D.; Yoo, S. J.; Baumgarten, M.; Kim, J. J.; Mullen, K. Pyrene based materials for exceptionally deep blue OLEDs. J. Mater. Chem. C 2014, 2, 9083–9086. (30) Fasel, R.; Beljonne, D.; Ruffieux, P.; Liu, J.; Giannakopoulos, A.; Tan, Y.-Z.; M¨ ullen, K.; Sanchez-Sanchez, C.; Li, B.-W.; Feng, X. Toward Cove-Edged Low Band Gap Graphene Nanoribbons. J. Am. Chem. Soc. 2015, 137, 6097–6103. (31) Segawa, Y.; Yagi, A.; Matsui, K.; Itami, K. Design and Synthesis of Carbon Nanotube Segments. Angew. Chem., Int. Ed. 2016, 55, 5136–5158. (32) Li, X. G.; Liao, Y.; Huang, M. R.; Kaner, R. B. Efficient synthesis of oligofluoranthene nanorods with tunable functionalities. Chem. Sci. 2015, 6, 7190–7200. 27



(33) Fuchibe, K.; Morikawa, T.; Shigeno, K.; Fujita, T.; Ichikawa, J. Pinpoint-fluorinated phenacenes: New synthesis and solubility enhancement strategies. Org. Lett. 2015, 17, 1126–1129. (34) Kawasumi, K.; Zhang, Q.; Segawa, Y.; Scott, L. T.; Itami, K. A grossly warped nanographene and the consequences of multiple odd-membered-ring defects. Nat. Chem. 2013, 5, 739–744. (35) Cui, X.; Xiao, C.; Zhang, L.; Li, Y.; Wang, Z. Polycyclic aromatic hydrocarbons with orthogonal tetraimides as n-type semiconductors. Chem. Commun. 2016, 52, 13209– 13212. (36) Ley, S. V.; Thomas, A. W. Modern Synthetic Methods for Copper-Mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S Bond Formation. Angew. Chem., Int. Ed. 2003, 42, 5400– 5449. (37) Zhou, F.; Cai, Q. Recent advances in Copper-catalyzed asymmetric coupling reactions. Beilstein J. Org. Chem. 2015, 11, 2600–2615. (38) Lindley, J. Tetrahedron report number 163 : Copper assisted nucleophilic substitution of aryl halogen. Tetrahedron 1983, 40, 1433–1456. (39) Fanta, P. E. The Ullmann Synthesis of Biaryls. Chemical Reviews 1946, 38, 139–196. (40) Katritzky, A. R.; Fali, C. N.; Li, J. General and Efficient Approaches to Fused [1,2- a ]Pyrroles and [1,2- a ]Indoles . J. Org. Chem. 1997, 62, 4148–4154. (41) Weingarten, H. Mechanism of the Ullmann Condensation. J. Org. Chem. 1964, 29, 3624–3626. (42) Bergman, J.; Venemalm, L. Efficient Synthesis of 2-Chloro-, 2-Bromo-, and 2Iodoindole. J. Org. Chem. 1992, 57, 2495–2497.

28


Page 28 of 32

Page 29 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(43) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Copper-mediated intermolecular direct biaryl coupling. J. Am. Chem. Soc. 2011, 133, 2160–2162. (44) Mao, X.; Ma, X.; Zhang, S.; Hu, H.; Zhu, C.; Cheng, Y. Silver-catalyzed highly regioselective phosphonation of arenes bearing electron-withdrawing groups. Eur. J. Org. Chem. 2013, 4245–4248. (45) Anderson, J. M.; Kochi, J. K. Silver (I)-Catalyzed Oxidative Decarboxylation of Acids by Peroxydisulfate. the Role of Silver (II). J. Am. Chem. Soc. 1970, 92, 1651–1659. (46) Cady, G.; Burger, L.; Grosse, A.; Barber, E.; Sheldon, Z. Preparation of Fluorocarbons by Catalytic Fluorination of Hydrocarbons. Ind. Eng. Chem. 2005, 39, 290–292. ˇ (47) Goryunkov, A. A.; Markov, V. Y.; Boltalina, O. V.; Zemva, B.; Abdul-Sada, A. K.; Taylor, R. Reaction of silver(I) and (II) fluorides with C60: Thermodynamic control over fluorination level. J. Fluorine Chem. 2001, 112, 191–196. (48) Fischer, R. G.; Lancaster, J. E.; Zweig, A. New Method for Selective Monofluorination of Aromatics Using Silver Difluoride. J. Org. Chem 1980, 45, 3597–3603. (49) Lucier, G.; Shen, C.; Casteel, W. J.; Chacón, L.; Barlett, N. Some chemistry of high oxidation state transition metal fluorides in anhydrous HF. J. Fluorine Chem. 1995, 72, 157–163. (50) Malinowski, P. J.; Derzsi, M.; Mazej, Z.; Jagliˇcić, Z.; Gawel, B.; LAsocha, W.; Grochala, W. AgIIso4: A genuine sulfate of divalent silver with anomalously strong onedimensional antiferromagnetic Interactions. Angew. Chem., Int. Ed. 2010, 49, 1683– 1686. (51) Polczy´ nski, P.; Jurczakowski, R.; Grochala, W. Stabilization and strong oxidizing properties of Ag(II) in a fluorine-free solvent. Chem. Commun. 2013, 49, 7480–7482.

29



(52) Budniak, A. K.; Masny, M.; Prezelj, K.; Grzeszkiewicz, M.; Gawraczy´ nski, J.; Dobrzycki, L.; Cyra´ nski, M. K.; Ko´zmi´ nski, W.; Mazej, Z.; Fijalkowski, K. J.; Grochala, W.; Leszczy´ nski, P. J. Reconnaissance of reactivity of an Ag(II)SO4 one-electron oxidizer towards naphthalene derivatives. New J. Chem. 2017, 41, 10742–10749. (53) Leszczy´ nski, P. J.; Budniak, A. K.; Grzeszkiewicz, M.; Gawraczy´ nski, J.; Dobrzycki,; Malinowski, P. J.; Jaro´ n, T.; Cyra´ nski, M. K.; Szarek, P.; Mazej, Z.; Grochala, W. Insights into reactivity patterns of Ag(II)SO4 with respect to fluoro- and trifluoromethylsubstituted aromatics. J. Fluorine Chem. 2019, 218, 105–110. (54) Urba´ nczyk, M.; Shchukina, A.; Golowicz, D.; Kazimierczuk, K. TReNDS - Software for reaction monitoring with time-resolved non-uniform sampling. Magn. Reson. Chem. 2018, 57, 4–12. (55) Polczy´ nski, P.; Gilewski, T. E.; Gawraczy´ nski, J.; Derzsi, M.; Leszczy´ nski, P. J.; Gadomski, W.; Mazej, Z.; Jurczakowski, R.; Grochala, W. Efficient Electrosynthesis of AgIISO4: A Powerful Oxidizer and Narrow Band Gap Semiconductor. Eur. J. Inorg. Chem. 2016, 2016, 5401–5404. (56) Urbaczyk, M.; Bernin, D.; Ko´zmi´ nski, W.; Kazimierczuk, K. Iterative Thresholding Algorithm for Multiexponential Decay Applied to PGSE NMR Data. Anal. Chem. 2013, 85, 1828–1833. (57) Delaglio, F.; Grzesiek, S.; Vuister, G. W.; Zhu, G.; Pfeifer, J.; Bax, A. NMRPipe: A multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR 1995, 6, 277–293. (58) Goddard ST. D., K. D. G. Sparky 3; University California, San Francisco. https: //www.cgl.ucsf.edu/home/sparky/, 2004. (59) Maciejewski, M. W.; Schuyler, A. D.; Gryk, M. R.; Moraru, I. I.; Romero, P. R.;

30


Page 30 of 32

Page 31 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Ulrich, E. L.; Eghbalnia, H. R.; Livny, M.; Delaglio, F.; Hoch, J. C. NMRbox: A Resource for Biomolecular NMR Computation. Biophys. J. 2017, 112, 1529 – 1534. (60) Dass, R.; Kasprzak, P.; Kazimierczuk, K. Quick, sensitive serial NMR experiments with Radon transform. J. Magn. Reson. 2017, 282, 114–118. (61) Najbauer, E. E.; Andreas, L. B. Correcting for magnetic field drift in magic-angle spinning NMR datasets. J. Magn. Reson. 2019, 305, 1–4. (62) Orekhov, V. Y.; Jaravine, V.; Mayzel, M.; Kazimierczuk, K. MddNMR - Reconstruction of NMR spectra from NUS signal using MDD and CS. 2004-2019; http://mddnmr. spektrino.com. (63) Markham, G. D.; Norrby, P. O.; Bock, C. W. S-Adenosylmethionine conformations in solution and in protein complexes: Conformational influences of the sulfonium group. Biochemistry 2002, 41, 7636–7646. (64) Johnston, E. R.; Dellwo, M. J.; Hendrix, J. Quantitative 2D exchange spectroscopy using time-proportional phase incrementation. J. Magn. Reson. (1969) 1986, 66, 399– 409. (65) Lu, J.; Hu, J.; Tang, W.; Zhu, D. Derivatives Binding To Cytochrome C. Dalton Trans. 1998, 1, 2267–2273. (66) Eberson, L. Electron Transfer Reactions in Organic Chemistry; Springer-Verlag: New York, 1987; Vol. 25; p 44. (67) Wayner, D. D.; McPhee, D. J.; Griller, D. Oxidation and Reduction Potentials of Transient Free Radicals. J. Am. Chem. Soc. 1988, 110, 132–137.

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Non-stationary 2D NMR - a novel method for studying reaction

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